Population-based pharmacogenomic assessment of QT prolongation
基于人群的 QT 延长药物基因组学评估
基本信息
- 批准号:9925250
- 负责人:
- 金额:$ 75.46万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-07-01 至 2022-04-30
- 项目状态:已结题
- 来源:
- 关键词:6-MercaptopurineAddressAdultAfrican AmericanAgingAlternative TherapiesAmericanAntibioticsAntidepressive AgentsAntifungal AgentsAsiansBiologicalCYP2C19 geneCaliforniaCandidate Disease GeneCarbamazepineCardiacCardiotoxicityCardiovascular systemCaucasiansClinicCollaborationsComplementCross-Sectional StudiesDataDatabasesDrug InteractionsElectrocardiogramEnvironmentEquationEthnic groupEuropeanExposure toGenesGeneticGenetic Predisposition to DiseaseGenetic studyGenotypeGoalsHLA-B AntigensHealthHeartHeterogeneityIndividualInpatientsInvestigationIon ChannelLabelLatinoLightLinkLiteratureMeasuresMediatingMediationMeta-AnalysisMinority GroupsModelingNamesOutcomeOutpatientsPacific Island AmericansPathway interactionsPatientsPersonsPharmaceutical PreparationsPharmacogeneticsPharmacogenomicsPharmacologyPharmacy facilityPhenotypePhysiciansPopulationPopulation HeterogeneityPredispositionQuantitative Trait LociResearchResearch PersonnelRiskSamplingStructureSudden DeathTPMT geneTestingTherapeuticTime StudyTissuesTorsades de PointesTranslatingUnited KingdomVariantVentricular ArrhythmiaWorkabacaviradjudicateadverse drug reactionadverse event riskadverse outcomebiobankbioinformatics toolclinically relevantclinically significantclopidogrelcohortdata resourcedesigndrug metabolismdrug withdrawalepidemiology studyethnic diversitygenetic epidemiologygenetic predictorsgenetic testinggenetic variantgenome wide association studygenome-widegenomic locushealth planheart rhythmlongitudinal analysismembernovelpopulation basedpreventprogramsside effect
项目摘要
Abstract
Cardiotoxicity of commonly prescribed medications, typically assessed by electrocardiographic features such
as prolongation of the QT interval, is a relevant clinical topic because it has regulatory consequences (labelling
and withdrawal of drugs) and is associated with potentially fatal patient-level outcomes (ventricular arrhythmias
and Torsade de Pointes). We propose here to leverage the extensive phenotypic and genotypic data resources
of the Kaiser Permanente Northern California (KPNC) Research Program on Genes, Environment and Health
(RPGEH), and the ability to link these data to other health plan databases, namely our pharmacy,
electrocardiogram (ECG) and outpatient/inpatient utilization databases. In particular, we will use the Genetic
Epidemiology Research in Adult Health and Aging (GERA) cohort members (n=110,266; n=69,276 with 1 or
more available ECGs; 52,667 with two or more ECGs). Our ability to conduct longitudinal analyses of the QT
interval over up to 20 years in a large and ethnically diverse population (The GERA cohort is 78% Caucasian,
6% Asian/Pacific Islander, 6% Latino, 3% African-American, 5% other or mixed) and to identify and
characterize genetic loci that influence adverse drug reactions is unique and will advance our understanding of
the genetic basis of cardiac toxicity of commonly prescribed medications. Replication of findings in Europeans
will be sought in 70,944 Caucasian subjects with ECG, genome-wide and medication data in the UK Biobank.
We will perform functional annotation of replicated hits to shed light on biological pathways and tissues
involved. In addition, to complement this approach and to more fully address the downstream clinical
significance of QT prolongation, we will also examine: a) genetic predictors of incident ventricular arrhythmias
and of Torsade de Pointes; b) whether the identified gene by drug interactions are associated with these
adverse outcomes and c) degree of mediation by QTc prolongation. Our results will be shared with the
Pharmacogenomics Research Network (PGRN) for replication and meta-analytical purposes. Our long-term
goal is to advance the field of the genetic basis of drug cardiotoxicity and its downstream
consequences that will inform therapeutic considerations.
摘要
通常通过心电图特征(如
作为QT间期延长,是一个相关的临床主题,因为它具有监管后果(标签
和停药),并与潜在的致命性患者水平的结果(室性心律失常
和尖端扭转型室性心动过速)。我们建议利用广泛的表型和基因型数据资源
凯泽永久北方加州(KPNC)基因,环境和健康研究计划
(RPGEH),并能够将这些数据链接到其他健康计划数据库,即我们的药房,
心电图(ECG)和门诊/住院使用数据库。特别是,我们将使用遗传
成人健康和老龄化流行病学研究(GERA)队列成员(n= 110,266; n= 69,276,1或
更多可用ECG; 52,667例有两个或更多ECG)。我们对QT进行纵向分析的能力
间隔长达20年的大型和种族多样化的人群(GERA队列是78%的白人,
6%亚洲/太平洋岛民,6%拉丁美洲人,3%非洲裔美国人,5%其他或混合),并确定和
描述影响药物不良反应的遗传位点是独特的,将促进我们对药物不良反应的理解。
常见处方药心脏毒性的遗传基础。在欧洲人中复制研究结果
将在英国生物库中的70,944名具有ECG、全基因组和药物数据的高加索受试者中进行研究。
我们将对复制的命中进行功能注释,以阐明生物途径和组织
涉案此外,为了补充这种方法并更全面地解决下游临床问题,
QT间期延长的意义,我们还将研究:a)发生室性心律失常的遗传预测因子
和尖端扭转型室性心动过速; B)通过药物相互作用鉴定的基因是否与这些相关
不良结局和c)QTc延长的介导程度。我们的成果将与
药物基因组学研究网络(PGRN),用于复制和荟萃分析目的。我们的长期
目标是推进药物心脏毒性及其下游遗传基础领域的研究。
这些结果将为治疗考虑提供信息。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Carlos Iribarren其他文献
Carlos Iribarren的其他文献
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{{ truncateString('Carlos Iribarren', 18)}}的其他基金
Multiethnic Study of Breast Arterial Calcium Gradation and CVD
乳腺动脉钙分级和 CVD 的多种族研究
- 批准号:
8330761 - 财政年份:2011
- 资助金额:
$ 75.46万 - 项目类别:
Multiethnic Study of Breast Arterial Calcium Gradation and CVD
乳腺动脉钙分级和 CVD 的多种族研究
- 批准号:
8461688 - 财政年份:2011
- 资助金额:
$ 75.46万 - 项目类别:
Multiethnic Study of Breast Arterial Calcium Gradation and CVD
乳腺动脉钙分级和 CVD 的多种族研究
- 批准号:
8838853 - 财政年份:2011
- 资助金额:
$ 75.46万 - 项目类别:
Multiethnic Study of Breast Arterial Calcium Gradation and CVD
乳腺动脉钙分级和 CVD 的多种族研究
- 批准号:
8188352 - 财政年份:2011
- 资助金额:
$ 75.46万 - 项目类别:
Clinical Core - Pharmacogenomics of Statin Therapy (POST)
临床核心 - 他汀类药物治疗的药物基因组学 (POST)
- 批准号:
8934880 - 财政年份:
- 资助金额:
$ 75.46万 - 项目类别:
Clinical Core - Pharmacogenomics of Statin Therapy (POST)
临床核心 - 他汀类药物治疗的药物基因组学 (POST)
- 批准号:
9326329 - 财政年份:
- 资助金额:
$ 75.46万 - 项目类别:
Clinical Core - Pharmacogenomics of Statin Therapy (POST)
临床核心 - 他汀类药物治疗的药物基因组学 (POST)
- 批准号:
9139484 - 财政年份:
- 资助金额:
$ 75.46万 - 项目类别:
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